1. Field of the Invention
The present invention relates to compounds having inhibitory activity against the biosynthesis of triglycerides and inhibitory activity against the secretion of lipoprotein containing apolipoprotein B, and prophylactic or therapeutic agents for hyperlipidemia comprising the same.
2. Background Art
A change in eating habits and an increase in the aged population have resulted in increased arteriosclerotic diseases. One of major risk factors of this group of diseases is an abnormal increase in cholesterol or triglycerides (hyperlipidemia). For example, the proportion of familial composite hyperlipidemia (FCHL) in patients suffering from cardiac infarction is about 30% which is higher than other basal diseases, and hyperlipidemia is known to be a basal disease which has a high risk of onset of ischemic heart disease (Lipid, 2, 373 (1991)).
Further, hyperlipidemia, which is a complication of obesity or diabetes, has been recognized as a risk factor of arteriosclerosis (Diabetes, 37, 1595(1988) and Int. J. Obesity, 15, 1 (1991).
Among various types of hyperlipidemia, hypertriglyceridemia is known to involve a complication of pancreatitis or the like (Medical Practice, 12, 957 (1995)).
Therefore, the treatment of hyperlipidemia is important for the prevention or treatment of arteriosclerotic diseases, such as ischemic heart diseases and cerebrovascular diseases, or pancreatitis. Further, it has been pointed out that there is a possibility that hyperlipidemia involved in renal diseases progresses renal disorders (Molecular Medicine, 31, 536(1994)). This has led to a proposal on the necessity of treating hyperlipidemia.
For the treatment or prevention of hyperlipidemia and arteriosclerotic diseases, medicaments for inhibiting the biosynthesis of cholesterol, particularly statin compounds (such as lovastatin) as medicaments for inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase and fibrate compounds (such as bezafibrate) as medicaments for reducing the level of triglycerides have been clinically used as pharmaceuticals.
Further, in recent years, reducing the serum triglyceride value and the level of serum apolipoprotein B-containing lipoprotein, which has been considered to induce arteriosclerosis, is expected to be effective in preventing or treating the above diseases (Arterioscler. Thromb., 12, 1284 (1992) and Circulation, 85, 37 (1992)). One of bases for this is that arteriosclerosis is not developed in patients suffering from xcex2-alipoproteinemia, from whom apolipoprotein B-containing lipoprotein is not detected in blood (Clin. Chem., 34, B9-12 (1988).
Pyrrolecarboxylic acid derivatives, sulfonamide derivatives, biphenyl-2-carboxylic acid derivatives, phenylpiperazine derivatives and the like are known as compounds having the above activity. Further, isoindolone derivatives having a substituent only in their nitrogen atom at the 2-position are known (EP643057A1 and W096/26205).
On the other hand, compounds having piperazine on the benzene in the isoindolone and isoquinolone skeletons are known (WO96/26187). These compounds, however, are different from the compounds of the present invention in the substituent of nitrogen at the 2-position, and, in addition, have activity as fibrinogen receptor antagonist. Therefore, they and the present invention are different form each other in idea.
So far as the present inventors know, compounds having inhibitory activity against the secretion of apolipoprotein B-containing lipoprotein among the compounds having piperazine on the benzene ring in the isoindolone and isoquinoline skeletons are not known.
Accordingly, the development of medicaments, which have activity to reduce the level of serum triglycerides and, based on a novel mechanism of action, activity to reduce the level of apolipoprotein B-containing lipoprotein in blood and, at the same time, do not cause any side effect of the accumulation of lipid such as found in xcex2-alipoproteinemia within the liver, have been desired for use of these medicaments as prophylactic or therapeutic agents for hyperlipidemia or arteriosclerotic diseases, (The Metabolic Basis of Inherited Disease, Sixth edition, 1139 (1989)).
The present inventors have now found that novel nitrogen-containing heterocyclic compounds having piperazine on a benzene ring of isoindolone and isoquinolone skeletons or skeletons similar thereto have high activity to reduce the level of lipid in blood, particularly high activity to reduce the level of triglycerides in blood and high activity to reduce the level of lipoprotein containing apolipoprotein B in blood by virtue of inhibitory activity against the biosynthesis of triglycerides and inhibitory activity against the secretion of lipoprotein containing apolipoprotein B in the liver, and thus are useful as therapeutic and prophylactic agents for hyperlipidemia, arteriosclerotic diseases, and pancreatitis.
Thus, according to the present invention, there is provided a compound represented by formula (I) and pharmaceutically acceptable salt and solvate thereof: 
wherein
A represents
group xe2x80x94CR1R2xe2x80x94(CH2)ixe2x80x94 wherein R1 and R2, which may be the same or different, each represent a hydrogen atom or alkyl having 1 to 6 carbon atoms and i is an integer of 0 or 1,
xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94Oxe2x80x94CH2xe2x80x94, or
xe2x80x94S(O)jxe2x80x94CH2xe2x80x94 wherein j is an integer of 0 to 2;
B represents a hydrogen or halogen atom;
X represents
xe2x80x94CR3R4R5 wherein R3, R4, and R5, which may be the same or different, each represent a hydrogen atom or phenyl, provided that any one of R3, R4, and R5 represents phenyl and one or more hydrogen atoms on phenyl may be substituted by a halogen atom, hydroxy, nitro, phenyl, or alkoxy having 1 to 6 carbon atoms,
xe2x80x94NR6R7 wherein R6 and R7, which may be the same or different, each represent a hydrogen atom, phenyl, or benzyl,
xe2x80x94(CH2xe2x80x94CHxe2x95x90C(CH3)xe2x80x94CH2)pxe2x80x94CH2CHxe2x95x90C(CH3)2 wherein p is an integer of 0 to 2,
alkyl having 1 to 18 carbon atoms,
cycloalkyl having 3 to 8 carbon atoms,
optionally substituted phenyl,
optionally substituted cinnamyl, or
a five- or six-membered heteroaromatic ring containing up to two hetero atoms;
Y represents xe2x80x94(CH2)qxe2x80x94 wherein q is an integer of 1 to 6,
xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94NR8xe2x80x94 wherein R8 represents a hydrogen atom or alkyl having 1 to 6 carbon atoms,
an oxygen atom, or
a bond;
Z represents carbonyl or a bond;
K represents optionally substituted alkylene having 1 to 6 carbon atoms or a bond;
L represents xe2x80x94CHxe2x95x90CHxe2x80x94 or a bond; and
M represents a hydrogen atom,
optionally substituted alkyl having 1 to 6 carbon atoms, optionally substituted cycloalkyl having 3 to 8 carbon atoms,
optionally substituted phenyl,
optionally substituted five- or six-membered, saturated or unsaturated heterocyclic ring containing up to two hetero atoms,
optionally substituted biphenyl, or
optionally substituted diphenylmethyl.
The compounds represented by formula (I) according to the present invention inhibit the biosynthesis of triglycerides in the liver and inhibit the secretion of lipoprotein containing apolipoprotein B from the liver. Therefore, they can exhibit activity to reduce the level of serum triglycerides and activity to reduce the level of lipoprotein containing apolipoprotein B in blood and, at the same time, can prevent accumulation of lipid within hepatic cells.
Accordingly, the compounds represented by formula (I) and pharmacologically acceptable salts and solvates thereof according to the present invention are useful for the prevention or treatment of hyperlipidemia (particularly hyper-very-low-density-lipoproteinemia) and arteriosclerotic diseases, such as cardiac infarction, or pancreatitis induced by hyperlipidemia.
Definition
As used herein, the term xe2x80x9calkylxe2x80x9d or xe2x80x9calkoxyxe2x80x9d as a group or a part of a group means a straight chain or branched chain alkyl. The term xe2x80x9chalogenxe2x80x9d used herein means fluorine, chlorine, bromine, or iodine. The term xe2x80x9chetero atomxe2x80x9d used herein means a nitrogen, oxygen, or sulfur atom.
Compounds Represented by Formula (I)
In formula (I), A represents xe2x80x94CR1R2xe2x80x94(CH2)1xe2x80x94 wherein R1 and R2, which may be the same or different, each represent a hydrogen atom or alkyl having 1 to 6 carbon atoms and i is an integer of 0 or 1; xe2x80x94CHxe2x95x90CHxe2x80x94; xe2x80x94Oxe2x80x94CH2xe2x80x94; or xe2x80x94S(O), xe2x80x94CH2xe2x80x94 wherein j is an integer of 0 to 2. Preferably, A represents xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94.
In formula (I), B represents a hydrogen or halogen atom, preferably a hydrogen, fluorine, or chlorine atom.
X represents
xe2x80x94CR3R4R5 wherein R3, R4, and R5, which may be the same or different, each represent a hydrogen atom or phenyl, provided that any one of R3, R4, and R5 represents phenyl and one or more hydrogen atoms on phenyl may be substituted by a halogen atom, hydroxy, nitro, phenyl, or alkoxy having 1 to 6 carbon atoms;
xe2x80x94NR6R7 wherein R6 and R7, which may be the same or different, each represent a hydrogen atom, phenyl or benzyl;
xe2x80x94(CH2xe2x80x94CHxe2x95x90C(CH3)xe2x80x94CH2)pxe2x80x94CH2CHxe2x95x90C(CH3)2 wherein p is an integer of 0 to 2;
alkyl having 1 to 18 carbon atoms;
cycloalkyl having 3 to 8 carbon atoms;
optionally substituted phenyl;
optionally substituted cinnamyl; or
a five- or six-membered aromatic ring having up to two hetero atoms.
Preferred examples of group xe2x80x94CR3R4R5 represented by X include those wherein one or two of R3, R4, and R5 represent phenyl with the remaining one representing a hydrogen atom and the phenyl may be unsubstituted, or alternatively one hydrogen atom on the phenyl may be substituted by a fluorine or chlorine atom.
Preferred examples of group xe2x80x94NR6R7 represented by X include those wherein R6 and R7 each represent phenyl or benzyl.
Preferred examples of group xe2x80x94(CH2xe2x80x94CHxe2x95x90C(CH3)xe2x80x94CH2)pxe2x80x94CH2CHxe2x95x90C(CH3)2 represented by X include those wherein p is 1 or 2.
The alkyl having 1 to 18 carbon atoms represented by X is preferably alkyl having 1 to 12 carbon atoms, more preferably alkyl having 1 to 6 carbon atoms.
The cycloalkyl having 3 to 8 carbon atoms represented by X is preferably cycloalkyl having 3 to 7 carbon atoms, and preferred examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
One or more hydrogen atoms on phenyl represented by X may be substituted, and an example of substituents usable herein is a group selected from the group consisting of hydroxy, halogens (preferably fluorine, chlorine, and bromine) atoms, nitro, alkoxys having 1 to 6 carbon atoms (preferably methoxy and ethoxy), and phenyl. When there are a plurality of substituents, they may be the same or different.
One or more hydrogen atoms on cinnamyl represented by X may be substituted, and an example of substituents usable herein is a group selected from the group consisting of hydroxy, halogens (preferably fluorine, chlorine, and bromine) atoms, nitro, phenyl, and alkoxys having 1 to 6 carbon atoms (preferably methoxy and ethoxy). When there are a plurality of substituents, they may be the same or different.
An example of preferred five- or six-membered heteroaromatic rings containing up to two hetero atoms represented by X is a ring selected from the group consisting of pyridine, thiophene, pyrrole, furan, pyrazole, imidazole, oxazole, thiazole, pyran, pyridazine, pyrimidine, and pyrazine. More preferred examples thereof include pyridine, thiophene, furan, imidazole, oxazole, and thiazole.
In formula (I), Y represents xe2x80x94(CH2)q wherein q is an integer of 1 to 6; xe2x80x94CHxe2x95x90CHxe2x80x94; xe2x80x94NR8xe2x80x94 wherein R8 represents a hydrogen atom or alkyl having 1 to 6 carbon atoms, an oxygen atom, or a bond. Preferably, Y represents xe2x80x94(CH2)qxe2x80x94 wherein q is an integer of 1 to 6; xe2x80x94NHxe2x80x94; an oxygen atom, or a bond.
Z represents carbonyl or a bond.
In formula (I), K represents an optionally substituted alkylene having 1 to 6 carbon atoms or a bond, preferably an optionally substituted alkylene having 1 to 3 carbon atoms or a bond.
One or more hydrogen atoms on the alkylene may be substituted, and an examples of substituents usable herein is a group selected from the group consisting of hydroxy, halogens (preferably fluorine, chlorine, and bromine) atoms, alkyl having 1 to 6 carbon atoms, and alkoxys having 1 to 6 carbon atoms (preferably methoxy and ethoxy). When there are a plurality of substituents, they may be the same or different.
L represents xe2x80x94CHxe2x95x90CHxe2x80x94 or a bond.
M represents a hydrogen atom, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, phenyl, a five- or six-membered heterocyclic ring containing up to two hetero atoms, biphenyl, or diphenylmethyl, preferably a hydrogen atom, cycloalkyl having 3 to 8 carbon atoms, phenyl, five- or six-membered, saturated or unsaturated heterocyclic ring containing up to two hetero atoms.
One or more hydrogen atoms on the alkyl represented by M may be substituted, and an example of substituents usable herein is a group selected from the group consisting of hydroxyl, halogens (preferably fluorine, chlorine, and bromine) atoms, amino, alkoxys having 1 to 6 carbon atoms (preferably methoxy and ethoxy), and alkoxycarbonyls having 1 to 4 carbon atoms (preferably methoxycarbonyl and ethoxycarbonyl). When there are a plurality of substituents, they may be the same or different.
One or more hydrogen atoms on the cycloalkyl having 3 to 8 carbon atoms represented by M may be substituted, and an example of substituents usable herein is a group selected from the group consisting of hydroxy, halogens (preferably fluorine, chlorine, and bromine) atoms, amino, alkoxys having 1 to 6 carbon atoms (preferably methoxy and ethoxy), alkylcarbonyloxys having 1 to 4 carbon atoms (preferably acetoxy and ethylcarbonyloxy), and alkoxycarbonyls having 1 to 4 carbon atoms (preferably, methoxycarbonyl and ethoxycarbonyl). When there are a plurality of substituents, they may be the same or different.
One or more hydrogen atoms on the benzene ring having phenyl, biphenyl, or diphenylmethyl represented by M may be substituted, and an example of substituents usable herein is a group selected from the group consisting of alkyls having 1 to 4 carbon atoms, trifluoromethyl, nitro, hydroxyl, halogens (preferably fluorine, chlorine, and bromine) atoms, amino, alkoxys having 1 to 4 carbon atoms (preferably methoxy and ethoxy), alkylcarbonyls having 1 to 4 carbon atoms (preferaby acetyl and ethylcarbonyl), and alkoxycarbonyls having 1 to 4 carbon atoms (preferably methoxycarbonyl and ethoxycarbonyl). When there are a plurality of substituents, they may be the same or different.
An example of five- or six-membered, saturated or unsaturated heterocyclic rings containing up to two hetero atoms represented by M is a ring selected from the group consisting of pyridine, thiophene, pyrrole, furan, pyrazole, imidazole, oxazole, thiazole, pyran, pyridazine, pyrimidine, pyrazine, and oxane. Preferred examples thereof include pyridine, thiophene, furan, imidazole, oxazole, thiazole, and oxane. One or more hydrogen atoms on the heterocyclic ring represented by M may be substituted, and examples of substituents usable herein include alkyls having 1 to 4 carbon atoms. When there are a plurality of substituents, they may be the same or different.
Examples of preferred groups represented by formula Xxe2x80x94Yxe2x80x94Zxe2x80x94 include (a) dibenzylaminoethyl, (b) isoprenyl, (c) geranyl, (d) farnesyl, (e) t-butyloxycarbonyl, (f) ethoxycarbonyl, (g) pivaloyl, (h) cyclohexyl methyl, (i) pyridylmethyl, (j) nicotinoyl, (k) thienylmethyl, (l) benzyl, (m) benzoyl, (n) benzyloxycarbonyl, (o) phenylpropyl, (p) cinnamyl, (q) biphenyl, (r) biphenylmethyl, (s) diphenyl C1-4 alkyl, (t) diphenylmethylcarbonyl, and (u) benzhydryloxycarbonyl. In this case, one or more hydrogen atoms on the benzene ring in (l) benzyl, (m) benzoyl, (n) benzyloxycarbonyl, (o) phenylpropyl, (p) cinnamyl, (q) biphenyl, (r) biphenylmethyl, (s) diphenyl C1-4 alkyl, (t) diphenylmethylcarbonyl, and (u) benzhydryloxycarbonyl may be substituted, and examples of substituents usable herein include hydroxy, halogens (preferably fluorine, chlorine, and bromine) atoms, nitro, and C1-C6 alkoxys (preferably methoxy and ethoxy).
Examples of preferred groups represented by formula xe2x80x94Kxe2x80x94Lxe2x80x94M include:
cycloalkyls having 3 to 8 carbon atoms wherein one or more hydrogen atoms on the cycloalkyl may be substituted by hydroxy or acyloxy having 1 to 4 carbon atoms;
phenyl-C1-6 alkylene- wherein one or more hydrogen atoms on the phenyl or alkylene may be substituted by hydroxy, a halogen atom, alkoxy having 1 to 6 carbon atoms, nitro, alkyl having 1 to 4 carbon atoms, trifluoromethyl, or alkoxycarbonyl having 1 to 4 carbon atom;
C3-8 cycloalkyl-C1-6 alkylene wherein one or more hydrogen atoms on the cycloalkyl may be substituted by hydroxy or acyloxy having 1 to 4 carbon atoms;
alkyls having 1 to 6 carbon atoms wherein one or more hydrogen atoms in the alkyl may be substituted by alkoxycarbonyl having 1 to 4 carbon atoms;
allyl;
cinnamyl;
a five- or six-membered heterocylic ring containing up to two hetero atoms-C1-6 alkylene- wherein one or more hydrogen atoms on the heterocyclic ring may be substituted by alkyl having 1 to 4 carbon atoms;
diphenylmethyl-C1-6 alkylene-; and
biphenyl-C1-6 alkylene-.
Among the compounds represented by formula (I) according to the present invention, a group of preferred compounds include compounds wherein
A represents group xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94;
B represents a hydrogen or halogen atom;
X represents xe2x80x94CR3R4R5 wherein R3, R4, and R5 each are as defined above in connection with formula (I),
xe2x80x94NR6R7 wherein R6 and R7 each are as defined above in connection with formula (I),
xe2x80x94(CH2xe2x80x94CHxe2x95x90C(CH3)pxe2x80x94CH2)pxe2x80x94CH2CHxe2x95x90C(CH3)2 wherein p is as defined above in connection with formula (I),
alkyl having 1 to 18 carbon atoms,
cycloalkyl having 3 to 8 carbon atoms,
optionally substituted phenyl, optionally substituted cinnamyl, or
a five- or six-membered aromatic ring containing up to two hetero atoms;
Y represents xe2x80x94(CH2)1xe2x80x94 wherein q is as defined above in connection with formula (I),
xe2x80x94NHxe2x80x94,
an oxygen atom, or
a bond;
Z represents carbonyl or a bond;
K represents optionally substituted alkylene having 1 to 6 carbon atoms or a bond;
L represents xe2x80x94CHxe2x95x90CHxe2x80x94 or a bond; and
M represents a hydrogen atom,
optionally substituted alkyl having 1 to 6 carbon atoms, optionally substituted cycloalkyl having 3 to 8 carbon atoms, optionally substituted phenyl,
an optionally substituted five- or six-membered,
saturated or unsaturated heterocyclic ring containing up to two hetero atoms,
optionally substituted biphenyl, or
optionally substituted diphenylmethyl.
According to a preferred embodiment of the present invention, a group of preferred compounds represented by formula (I) according to the present invention include a group of compounds represented by formula (II): 
wherein A, B, X, Z, K, L, and M each are as defined above in connection with formula (I); and Y represents xe2x80x94(CH2)1xe2x80x94 with q being an integer of 1 to 6, xe2x80x94NHxe2x80x94, an oxygen atom, or a bond, provided that compounds, wherein xe2x80x94Kxe2x80x94Lxe2x80x94M represents xe2x80x94H, are excluded.
Among the group of compounds represented by formula (II), a group of further preferred compounds include compounds wherein
A represents group xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94;
as B represents a hydrogen or halogen atom;
X represents xe2x80x94CR3R4R5 wherein R3, R4, and R5 each are as defined above in connection with formula (I),
xe2x80x94NR6R7 wherein R6 and R7 each are as defined above in connection with formula (I),
xe2x80x94(CH2xe2x80x94CHxe2x95x90C(CH3)xe2x80x94CH2)pxe2x80x94CH2CHxe2x95x90C(CH3)2 wherein p is as defined above in connection with formula (I),
alkyl having 1 to 18 carbon atoms,
cycloalkyl having 3 to 8 carbon atoms,
optionally substituted phenyl,
optionally substituted cinnamyl, or
a five- or six-membered heteroaromatic ring containing up to two hetero atoms;
Y represents xe2x80x94(CH2)qxe2x80x94 with q being an integer of 1 to 6, xe2x80x94NHxe2x80x94, an oxygen atom, or a bond;
Z represents carbonyl or a bond;
K represents optionally substituted alkylene having 1 to 6 carbon atoms or a bond;
L represents xe2x80x94CHxe2x95x90CHxe2x80x94 or a bond; and
M represents a hydrogen atom,
optionally substituted alkyl having 1 to 6 carbon atoms,
optionally substituted cycloalkyl having 3 to 8 carbon atoms,
optionally substituted phenyl,
an optionally substituted five- or six-membered,
saturated or unsaturated heterocyclic ring containing up to two hetero atoms,
optionally substituted biphenyl, or
optionally substituted diphenylmethyl.
Further, a group of further preferred compounds represented by formula (II) include compounds wherein
A represents group xe2x80x94CR3R2xe2x80x94(CH2)ixe2x80x94 wherein R1 and R2, which may be the same or different, each represent a hydrogen atom or alkyl having 1 to 6 carbon atoms and i is an integer of 0 or 1,
xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94Oxe2x80x94CH2xe2x80x94, or
xe2x80x94S(O)jxe2x80x94CH2xe2x80x94 wherein j is an integer of 0 to 2;
B represents a hydrogen or halogen atom;
X represents xe2x80x94CR3R4R5 wherein R3, R4, and R5 each are as defined above in connection with formula (I) or
xe2x80x94(CH2xe2x80x94CHxe2x95x90C(CH3)xe2x80x94CH2)pxe2x80x94CH2CHxe2x95x90C(CH3), wherein p is as defined above in connection with formula (I);
Y represents xe2x80x94(CH2)qxe2x80x94 wherein q is an integer of 1 to 6,
xe2x80x94NHxe2x80x94,
an oxygen atom, or
a bond;
Z represents carbonyl or a bond;
K represents optionally substituted alkylene having 1 to 6 carbon atoms or a bond;
L represents xe2x80x94CHxe2x95x90CHxe2x80x94 or a bond; and
M represents a hydrogen atom,
optionally substituted alkyl having 1 to 6 carbon atoms,
optionally substituted cycloalkyl having 3 to 8 carbon atoms,
optionally substituted phenyl,
an optionally substituted, five- or six-membered,
saturated or unsaturated heterocyclic ring containing up to two hetero atoms,
optionally substituted biphenyl, or
optionally substituted diphenylmethyl.
Further, a group of further preferred compounds represented by formula (II) include compounds wherein
A represents group xe2x80x94CR3R2xe2x80x94(CH2)ixe2x80x94 wherein R1, R2, and i each are as defined above in connection with formula (I),
xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94Oxe2x80x94CH2xe2x80x94, or
xe2x80x94S(O)jxe2x80x94CH2xe2x80x94 wherein j is as defined above in connection with formula (I);
B represents a hydrogen or halogen atom;
X represents xe2x80x94CR3R4R5 wherein R3, R4, and R5 each are as defined above in connection with formula (I),
xe2x80x94NR6R7 wherein R6 and R7 each are as defined above in connection with formula (I),
xe2x80x94(CH2xe2x80x94CHxe2x95x90C(CH3)xe2x80x94CH2)pxe2x80x94CH2CHxe2x95x90C(CH3)2 wherein p is as defined above in connection with formula (I),
alkyl having 1 to 18 carbon atoms,
cycloalkyl having 3 to 8 carbon atoms,
optionally substituted phenyl,
optionally substituted cinnamyl, or
a five- or six-membered heteroaromatic ring containing up to two hetero atoms;
Y represents xe2x80x94(CH2)qxe2x80x94 wherein q is as defined in claim 1,
xe2x80x94NHxe2x80x94,
an oxygen atom, or
a bond,
Z represents carbonyl or a bond;
K represents optionally substituted alkylene having 1 to 3 carbon atoms or a bond;
L represents xe2x80x94CHxe2x95x90CHxe2x80x94 or a bond; and
M represents a hydrogen atom,
optionally substituted cycloalkyl having 3 to 8 carbon atoms,
optionally substituted phenyl, or
an optionally substituted, five- or six-membered heterocyclic ring containing up to two hetero atoms.
Specific examples of compounds represented by formula (I) according to the invention include
2-cyclohexyl-6-[4-(trans,trans-farnesyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
6-[4-(N,N-dibenzylaminoethyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
2-(4-acetoxy)cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-benzyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-cyclohexyl-6-[4-(2-diphenylethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-benzyl-6-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
3-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-1,3-benzoxazin-4-one,
2-cyclohexyl-6-[4-(geranyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(benzhydryl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-{4-[3,3-bis(4-chlorophenyl)-1-propyl]piperazin-1-yl}-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-4-fluoro-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-5-fluoro-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-7-fluoro-2,3-dihydro-1H-isoindol-1-one,
2-benzyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-cyclohexylmethyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxybenzyl)-2,3-dihydro-1H-isoindol-1-one,
2-(4-bromobenzyl)-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
Ethyl {6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1-oxo-1,3-dihydro-1H-isoindol-2-yl}acetate,
2-(4-chlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-cyclopropyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexylmethyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclopropylmethyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-(2-chlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-(3-chlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
6-[4-(benzhydryloxycarbonyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2H-isoquinolin-1-one,
2-cyclohexyl-6-{4-[3,3-bis(4-methoxyphenyl)-1-propyl]piperazin-1-yl}-2,3-dihydro-1H-isoindol-1-one,
2-benzyl-7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one,
2-(4-bromobenzyl)-6-(4-t-butoxycarbonylpiperazin-1-yl)-2,3-dihydro-1H-isoindol-1-one,
3-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-1,3-benzothiazin-4-one,
2-cyclopropylmethyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
7-chloro-2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
5-chloro-2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
4-chloro-2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclobutyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclopentyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cycloheptyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclobutylmethyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]2-2,3-dihydro-1H-isoindol-1-one,
2-cyclopentylmethyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cycloheptylmethyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclopropyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-cyclobutyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-cyclopentyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-cycloheptyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-cyclobutylmethyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-cyclopentylmethyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-cycloheptylmethyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-phenyl-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-hydroxyphenyl)-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-fluorophenyl)-2,3-dihydro-1H-isoindol-1-one,
2-(4-chlorophenyl)-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-(4-bromophenyl)-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-(4-aminophenyl)-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxyphenyl)-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxyphenyl)-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxycarbonylphenyl)-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxycarbonylphenyl)-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-hydroxybenzyl)-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-fluorobenzyl)-2,3-dihydro-1H-isoindol-1-one,
2-(4-chlorobenzyl)-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-(4-aminobenzyl)-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxybenzyl)-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxycarbonylbenzyl)-2,3-dihydro-1H-isoindol-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-phenyl-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-hydroxyphenyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-fluorophenyl)-3,4-dihydro-2H-isoquinolin-1-one,
2-(4-chlorophenyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-(4-bromophenyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-(4-aminophenyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxyphenyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxyphenyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxycarbonylphenyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxycarbonylphenyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-hydroxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-fluorobenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
2-(4-bromobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-(4-aminobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1-2-(4-methoxycarbonylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxycarbonylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
2-benzyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-4-fluoro-3,4-dihydro-2H-isoquinolin-1-one,
2-benzyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-5-fluoro-3,4-dihydro-2H-isoquinolin-1-one,
2-benzyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-7-fluoro-3,4-dihydro-2H-isoquinolin-1-one,
2-benzyl-4-chloro-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-benzyl-5-chloro-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-benzyl-7-chloro-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-4-fluoro-2-phenyl-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-5-fluoro-2-phenyl-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-7-fluoro-2-phenyl-3,4-dihydro-2H-isoquinolin-1-one,
2-cyclohexyl-6-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-benzyl-7-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-cyclopropyl-6-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclopropyl-7-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
6-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-2-phenyl-2,3-dihydro-1H-isoindol-1-one,
7-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-2-phenyl-3,4-dihydro-2H-isoquinolin-1-one,
6-[4-(benzyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
6-[4-(4-chlorobenzyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(3-pyridylmethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(octadecyl)piperazin-1-yl)-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(2-thenyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(cyclohexylmethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(4-methoxybenzyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(isoprenyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(4-fluorobenzyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(4-nitrobenzyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(3-phenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
6-[4-(cinnamyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3-chlorobenzyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
6-[4-(4-bromobenzyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
6-[4-(2-chlorobenzyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(triphenylmethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(3,4-dichlorobenzyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(4-biphenylmethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-hydroxy)cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
6-[4-(benzyloxycarbonyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(ethoxycarbonyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
6-[4-(t-butoxycarbonyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
6-[4-(benzoyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(pivaloyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(methoxybenzyloxycarbonyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(3,5-dimethoxy-4-hydroxybenzoyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(pyridine-3-carbonyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-diphenylacetylpiperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-6-[4-(4-hydroxyphenyl)methylpiperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-5-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cyclohexyl-5-[4-(trans, trans-farnesyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
6-[4-(t-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
6-[4-(t-butoxycarbonyl)piperazin-1-yl]-5-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,
6-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
6-(4-t-butoxycarbonylpiperazin-1-yl)-2-(4-chlorobenzyl)-2,3-dihydro-1H-isoindol-1-one,
6-(4-t-butoxycarbonylpiperazin-1-yl)-2-(4-methoxy-benzyl)-2,3-dihydro-1H-isoindol-1-one,
6-(4-t-butoxycarbonylpiperazin-1-yl)-2-cyclopropyl-methyl-2,3-dihydro-1H-isoindol-1-one,
6-(4-t-butoxycarbonylpiperazin-1-yl)-2-cyclohexyl-methyl-2,3-dihydro-1H-isoindol-1-one,
6-[4-(t-butoxycarbonyl)piperazin-1-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one,
6-(4-t-butoxycarbonylpiperazin-1-yl)-2-(4-nitro-benzyl)-2,3-dihydro-1H-isoindol-1-one,
Ethyl[6-(4-t-butoxycarbonylpiperazin-1-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]acetate,
2-cyclohexyl-7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one,
2-cyclohexyl-7-(4-t-butoxycarbonylpiperazin-1-yl)-2H-isoquinolin-1-one,
2-methyl-7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one,
2-cyclohexylmethyl-7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one,
2-cyclopropylmethyl-7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one,
2-(4-chlorobenzyl)-7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one,
7-(4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
3,3-dimethyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
3-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-1,3-benzoxazin-4-one,
2-cyclohexyl-6-[4-(2-diphenylamino-ethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
4-(2-cyclohexyl-1-oxo-2,3-dihydro-1H-isoindol-6-yl)piperazine-1-carboxylic acid benzhydrylamide,
7-[4-(benzhydryloxycarbonyl)piperazin-1-yl]-2-benzyl-3,4-dihydro-2H-isoquinolin-1-one,
2-benzyl-7-[4-(4-chlorobenzyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-isopropyl-2,3-dihydro-1H-isoindol-1-one,
2-alyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
2-cinnamyl-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-methoxybenzyl)-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-methylbenzyl)-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-trifluoromethylbenzyl)-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-nitrobenzyl)-2,3-dihydro-1H-isoindol-1-one,
6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(thiazol-4-yl)methyl-2,3-dihydro-1H-isoindol-1-one,
2-benzyl-3,3-dimethyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,
3,3-dimethyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(2-methylbenzyl)-2,3-dihydro-1H-isoindol-1-one,
3,3-dimethyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(1-phenylethyl)-2,3-dihydro-1H-isoindol-1-one,
2-allyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-cinnamyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-phenyl-1-propyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-phenetyl-3,4-dihydro-2H-isoquinolin-1-one,
2-(3,3-diphenyl-1-propyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(2-methylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-methylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
2-(3,4-dimethylbenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-(2,5-dimethylbenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(2,4,6-trimethylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(1-phenylethyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-trifluoromethylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-trifluoromethylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-fluorobenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
2-(3-bromobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-(3,4-dichlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-(2,4-dichlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-methoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
2-(3,5-dimethoxybenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-hydroxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one,
2-(3,5-dihydroxybenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-(2-hydroxy-2-phenyl)ethyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
2-(2-biphenylmethyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(tetrahydropyran-2-yl)methyl-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(thiazol-4-yl)methyl-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methylthiazol-5-yl)methyl-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(pyridine-4-yl)methyl-3,4-dihydro-2H-isoquinolin-1-one,
7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(pyridine-2-yl)methyl-3,4-dihydro-2H-isoquinolin-1-one, and
2-benzyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one.
The compounds according to the present invention may exist as salts. Preferred salts include pharmaceutically acceptable nontoxic salts, for example, lithium, sodium, potassium, magnesium, and calcium salts, salts with ammonia and suitable nontoxic amines, for example, C1-C6 alkylamines (for example, triethylamine) salts, C1-C6 alkanolamines (for example, diethanolamine or triethanolamine) salts, procaine salts, cyclohexylamine (for example, dicyclohexylamine) salts, benzylamine (for example, N-methylbenzylamine, N-ethylbenylamine, N-benzyl-xcex2-phenetylamine, N,N-dibenzylethylenediamine or dibenzylamine) salts, and heterocyclic amines (for example, morpholine or N-ethylpyridine) salts, hydrohalogenic acid salts, such as hydrofluoride salts, hydrochloride salts, hydrobromide salts, and hydroiodide salts, inorganic acid salts, such as sulfuric acid salts, nitric acid salts, phosphoric acid salts, perchloric acid salts, and carbonic acid salts, carboxylic acid salts, such as acetic acid salts, trichloroacetic acid salts, trifluoroacetic acid salts, hydroxyacetic acid salts, lactic acid salts, citric acid salts, tartaric acid salts, oxalic acid salts, benzoic acid salts, mandelic acid salts, butyric acid salts, maleic acid salts, propionic acid salts, formic acid salts, and malic acid salts, amino acid salts, such as alginic acid salts, aspartic acid salts, and glutamic acid salts, and other organic acid salts, such as methanesulfonic acid salts and p-toluenesulfonic acid salts. Preferred are acid addition salts, such as trifluoroacetic acid salts, hydrochloric acid salts, sulfuric acid salts, oxalic acid salts, methanesulfonic acid salts, and citric acid salts, and amino acid salts, such as glutamic acid salts and aspartic acid salts.
The compounds according to the present invention may exist as solvates. Preferred solvates include hydrates of the compounds and solvation products between the compounds and ethanol.
Use of Compounds Represented by Formula (I)/Pharmaceutical Composition
The compounds represented by formula (I) and pharmacologically acceptable salts and solvates thereof according to the present invention have triglyceride biosynthesis inhibitory activity and inhibitory activity against secretion of apolipoprotein B-containing lipoproteins in liver. Therefore, the compounds according to the present invention can lower the amount of serum triglycerides and serum apolipoprotein B-containing lipoproteins, and thus can be used as prophylactic or therapeutic agents for hyperlipidemia (particularly hyper-very-low-density-lipoproteinemia) and/or arteriosclerotic diseases, such as cardiac infarction, or pancreatitis induced by hyperlipidemia. The compounds represented by formula (I) according to the present invention are especially advantageous in that they inhibit biosynthesis of lipids within hepatic cells and hence are not considered to have such side effect as will cause accumulation of hepatolipids.
The compounds and pharmacologically acceptable salts and solvates thereof according to the present invention may be administered to human beings and animals other than human beings by way of any one of routes including oral and parenteral administration, such as intravenous injection, intramuscular injection, subcutaneous administration, intraperitoneal administration, rectal administration, or percutaneous administration.
Accordingly, the compounds and pharmacologically acceptable salts and solvates thereof according to the present invention may be formed into appropriate dosage forms depending on its administration routes, and specifically prepared primarily into any one of the preparation forms including injections such as intravenous injection and intramuscular injection, preparations for oral administration such as capsules, tablets, granules, powders, pills, particulates, and troches, preparations for rectal administration, fatty suppositories, and aqueous suppositories.
These preparations can be prepared by conventional methods with ordinarily used excipients, fillers, binders, humidifiers, disintegrants, surface active agents, lubricants, dispersants, buffers, preservatives, dissolution aids, antiseptics, flavoring agents, analgesic agents, stabilizers and the like. Such non-toxic additives usable herein include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose or a salt thereof, gum arabic, polyethylene glycol, syrup, petrolatum, glycerol, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, and sodium phosphate.
The content of the compound according to the present invention in the pharmaceutical composition may vary according to its dosage forms. In general, however, the content of the compound may be about 1 to 70% by weight, preferably about 5 to 50% by weight, based on the whole composition.
The dosage may be appropriately determined in consideration of the dosage route and the age, sex, condition of patients and the like, and the preparation may be administered for the treatment of hyperlipidemia usually in an amount of about 0.1 to 5000 mg, preferably 1 to 600 mg per day per adult in one or several portions.
Synthesis of Compounds Represented by Formula (I)
Preferably, the compounds represented by formula (I) according to the present invention are synthesized by the following synthesis processes 1 to 10. In the following synthesis, protective groups or C1-C4 acyl groups on substituents may be if necessary introduced and removed by conventional means.
It will be apparent to a person having ordinary skill in the art that, in the following production processes, the order of synthesis may be determined so as not to cause any side reaction in functional groups not involved in the reaction and, in addition, functional groups may be protected by a suitable protective group in order to prevent the progress of unfavorable reactions.
Synthesis Process 1
Among the compounds represented by formula (I), compounds, wherein A represents group xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94, are preferably produced by the following process. 
The first step is an imidation reaction of an acid anhydride. A compound represented by formula (VI), wherein t is an integer of 1 or 2 and B represents a hydrogen or halogen atom, may be reacted with a compound represented by formula H2Nxe2x80x94Kxe2x80x94Lxe2x80x94M, wherein K, L, and M each are as defined above in connection with formula (I), in the presence or absence of a base in a solvent not involved in the reaction (for example, tetrahydrofuran, benzene, toluene, or xylene) or under solvent-free conditions for 0.5 to 48 hr, preferably 1 to 24 hr, at 50 to 200xc2x0 C., preferably 100 to 180xc2x0 C., to obtain a compound represented by formula (VII) wherein t is an integer of 1 or 2 and B, K, L, and M each are as defined above in connection with formula (I).
The second step is a reduction reaction for converting the imide to a lactam. The compound represented by formula (VII) may be reduced in a solvent not involved in the reaction (for example, acetic acid, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, benzene, or toluene) in the presence of a reducing agent (for example, zinc-acetic acid, tin, sodium boron hydride, or zinc boron hydride) for 0.5 to 48 hr, preferably 1 to 24 hr, at 50 to 200xc2x0 C., preferably 80-150xc2x0 C., to obtain a compound represented by formula (VIII) wherein t, B, X, L, and M each are as defined above.
The third step is a nitration reaction. Conventional nitrating agents may be used in the nitration. The compound represented by formula (VIII) is reacted with a nitrating agent (preferably, nitric acid or potassium nitrate) in concentrated sulfuric acid for 0.5 to 48 hr, preferably 0.5 to 24 hr, at xe2x88x9220 to 100xc2x0 C., preferably xe2x88x9220 to 50xc2x0 C., to obtain a compound represented by formula (IX) wherein t, B, K, L, and M each are as defined above.
In the fourth step, the compound represented by formula (IX) is reduced to convert the nitro group to an amino group. Specifically, this conversion is carried out by catalytic reduction in the presence of palladium-carbon, palladium black, palladium hydroxide, platinum oxide, or Raney nickel, a reduction reaction using tin, zinc, iron or the like and an acid, such as acetic acid, or reduction with sodium boron hydride or hydrazine, preferably catalytic reduction in the presence of palladium-carbon or palladium black or a reduction reaction with iron and acetic acid, in a solvent not involved in the reaction (for example, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, or benzene) for 0.5 to 48 hr, preferably for 0.5 to 30 hr, at 0 to 100xc2x0 C., preferably 0 to 50xc2x0 C., to obtain a compound represented by formula (X) wherein t, B, K, L, and M each are as defined above.
The fifth step is piperazination of the amine. The compound represented by formula (X) is reacted in the presence of 1 to 5 equivalents of bischloroethylamine and in the presence or absence of 1 to 3 equivalents of an acid, such as hydrochloric acid, in a solvent not involved in the reaction (for example, n-butanol, xylene, or toluene) for 0.5 hr to 7 days, preferably 1 hr to 5 days, at 50 to 200xc2x0 C., preferably 60 to 180xc2x0 C., to obtain a compound represented by formula (XI) wherein t, B, K, L, and M each are as defined above.
The sixth step is a condensation reaction with a compound represented by formula Xxe2x80x94Yxe2x80x94Zxe2x80x94G. This reaction may be carried out by any one of the following methods (i) to (iii).
Method (i): A compound represented by formula Xxe2x80x94Yxe2x80x94Zxe2x80x94G, wherein G represents a halogen atom, such as chlorine, bromine, or iodine, C1-C4 alkylsulfonyl such as methanesulfonyl, or arylsulfonyl, such as p-toluenesulfonyl, X and Y each are as defined above in connection with formula (I), and z represents a bond, is reacted with the compound represented by formula (XI) in the presence or absence of a base in a solvent not involved in the reaction (for example, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, or dimethyl sulfoxide) for 10 min to 48 hr, preferably 10 min to 24 hr, at xe2x88x9220 to 150xc2x0 C., preferably 0-100xc2x0 C., to obtain a compound represented by formula (I) wherein A represents xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94, B, K, L, M, X, and Y each are as defined above in connection with formula (I), and z represents a bond).
Method (ii): The compound represented by formula Xxe2x80x94Yxe2x80x94Zxe2x80x94G, wherein X and Y are as defined above in connection with formula (I), Z represents carbonyl or, together with group G, represents a carboxylic acid residue which has been activated by an acid halide, an acid anhydride or an activator, is reacted with the compound represented by formula (XI) in the presence or absence of a base in a solvent not involved in the reaction (for example, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, or dioxane) for 1 min to 48 hr, preferably 1 min to 24 hr, at xe2x88x9220 to 100xc2x0 C., preferably 0 to 50xc2x0 C., to obtain a compound represented by formula (I) wherein A represents xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94, B, K, L, M, X, and Y each are as defined above in connection with formula (I), and Z represents carbonyl.
Method (iii): When the compound represented by formula Xxe2x80x94Yxe2x80x94Zxe2x80x94G is Xxe2x80x94(CH2)(qxe2x88x921)xe2x80x94CHO wherein q represents an integer of 1 to 6 and X is as defined above in connection with formula (I), this compound and the compound represented by formula (XI) may be subjected to reductive alkylation with 1 to 5 equivalents of a reducing agent, for example, a metal hydride reagent, such as sodium boron cyanohydride, lithium boron cyanohydride, sodium boron hydride, lithium boron hydride, or sodium boron triacetoxyhydride) in the presence or absence of 0.1 to 5 equivalents of an acid, such as acetic acid or hydrochloric acid, in a solvent not involved in the reaction (for example, dichloroethane, dichloromethane, or tetrahydrofuran) for 0.5 to 48 hr, preferably 1 to 24 hr, at xe2x88x9220 to 100xc2x0 C., preferably 0 to 70xc2x0 C., to obtain a compound represented by formula (I) wherein A represents xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94, B, K, L, M, and X each are defined above in connection with formula (I), Y represents xe2x80x94(CH2)qxe2x80x94 wherein q is an integer of 1 to 6, and Z represents a bond.
The compound represented by formula (VIII), wherein A represents xe2x80x94CH2CH2xe2x80x94, may also be synthesized by the method described in xe2x80x9cYakugaku Zasshi, 96, 176-179 (1976).
Bases usable in the reaction in synthesis process 1 include pyridine, triethylamine, N-methylmorpholine, and dimethylaminopyridine. Preferably, the base is used in an amount of 0.1 to 5 equivalents.
Preferred activators for carboxylic acids in the condensation of the compound represented by formula (XI) with the compound represented by Xxe2x80x94Yxe2x80x94Zxe2x80x94G in method (ii) include 1,3-dicyclohexylcarbodiimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
Synthesis Process 2
As described below, among the compounds represented by formula (I), compounds, wherein B represents a halogen atom, may be produced by halogenating a corresponding compound wherein B represents a hydrogen atom. 
Specifically, the compound represented by formula (I), wherein A, K, L, M, X, Y, and Z each are as defined above in connection with formula (I) and B represents a hydrogen atom), is halogenated using a radical initiator (for example, N-halosuccinimide, preferably N-chlorosuccinimide, or N-bromosuccinimide) preferably in the presence of 0.01 to 3 equivalents of 2,2xe2x80x2-azobisisobutyronitrile in a solvent not involved in the reaction (for example, carbon tetrachloride, tetrahydrofuran, or benzene) for 0.5 to 48 hr, preferably for 1 to 24 hr, at xe2x88x9220 to 150xc2x0 C., preferably at 0 to 120xc2x0 C. to give the compound represented by formula (I) wherein B represents a halogen atom.
Synthesis Process 3
Among the compounds represented by formula (I), compounds, wherein A represents xe2x80x94CHxe2x95x90CHxe2x80x94, may be produced by dehydrogenating corresponding compounds wherein A represents xe2x80x94CH2CH2xe2x80x94. 
Specifically, according to the method described in J. Med. Chem. 39, 4583-4591 (1996), the compound represented by formula (I), wherein B, K, L, M, X, Y, and Z each are as defined above in connection with formula (I) and A represents xe2x80x94CH2CH2xe2x80x94, may be dehydrogenated in the presence of palladium-carbon or palladium black in a solvent not involved in the reaction (for example, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, or benzene) for 0.5 to 48 hr, preferably for 0.5 to 30 hr. at 0 to 100xc2x0 C., preferably at 0 to 80xc2x0 C. to give the compound represented by formula (I) wherein A represents xe2x80x94CHxe2x95x90CHxe2x80x94.
Synthesis Process 4
Among the compounds represented by formula (I), compounds, wherein A represents group xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94, may also be produced preferably through route A or route B. 
Route A:
According to step 6 in synthesis process 1, a compound represented by formula (XII), wherein t is an integer of 1 or 2 and B is as defined above in connection with formula (I), is condensed with a compound represented by formula Xxe2x80x94Yxe2x80x94Zxe2x80x94G wherein X, Y, and Z each are as defined above in connection with formula (I), G represents a halogen atom, such as chlorine, bromine, or iodine, C1-C4 alkylsulfonyl, such as methanesulfonyl, or arylsulfonyl, such as p-toluenesulfonyl, thereby providing a compound represented by formula (XIII) wherein t is an integer of 1 or 2, B, X, Y, and Z each are as defined as above in connection with formula (I).
Next, according to the description of J. Med. Chem. 39, 4583-4591 (1996) or Synthesis, 79, 527-529 (1979), the compound represented by formula (XIII) is reacted with a compound represented by formula Gxe2x80x94Kxe2x80x94Lxe2x80x94M wherein G represents a halogen atom, such as chlorine, bromine, or iodine, C1-C4 alkylsulfonyl, such as methanesulfonyl, arylsulfonyl, such as p-toluenesulfonyl, and K, L, and M each are as defined above in connection with formula (I), thereby providing the compound represented by formula (I) wherein A represents group xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94.
Route B:
The compound represented by formula (XII) in its piperazine is protected by a protective group, followed by a reaction according to the method described in J. Med. Chem. 39, 4583-4591 (1996). Protective groups usable for piperazine include conventional protective groups commonly used in synthesis of peptides, and preferred examples thereof include t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trifluoroacetyl, allyloxycarbonyl and trityl. At the outset, the compound represented by formula (XII) in its piperazine portion is protected by a conventional method to give a compound represented by formula (XIV) wherein t is an integer of 1 or 2, B is as defined above in connection with formula (I) and P represents a protective group of amino. Next, the compound represented by formula (XIV) is reacted with a compound represented by formula Gxe2x80x94Kxe2x80x94Lxe2x80x94M, wherein G, K, L, and M each are as defined above in connection with route A, according the method described in the literature noted above, thereby providing a compound represented by formula (XV). The protective group in the compound represented by formula (XV) is removed by a conventional method to give a compound represented by formula (XI). The compound represented by formula (XI) is condensed with a compound represented by formula Xxe2x80x94Yxe2x80x94Zxe2x80x94G, wherein X, Y, Z, and G each are as defined above in connection with route A, according to step 6 in synthesis process 1, thereby providing the compound represented by formula (I) wherein A represents group xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94.
Synthesis Process 5
Among the compounds represented by formula (I), compounds, wherein A represents group xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94, may also be produced preferably by the following process. 
A compound represented by formula (XVI), wherein t is an integer of 1 or 2 and B is as defined above in connection with formula (I), is reacted with a compound represented by formula H2Nxe2x80x94Kxe2x80x94Lxe2x80x94M according to step 1 in synthesis process 1, thereby providing a compound represented by formula (XVII). The compound represented by formula (XVII) is then subjected to a reduction reaction using zinc and acetic acid according to step 2 in synthesis process 1 to give a compound represented by formula (XVIII). The acetamide thus obtained is hydrolyzed under acidic conditions to give a compound represented by formula (X). Thereafter, the compound represented by formula (I), wherein A represents group xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94, may be produced according to step 5 and later steps in synthesis process 1.
Synthesis Process 6
Among compounds represented by formula (I), compounds wherein A represents group xe2x80x94CR1R2xe2x80x94, where R1 and R2 each represent C1-C6 alkyl, may be synthesized by producing a compound represented by formula (XIX) according to the method described in Angew. Chem. Int. Ed. Engl. 7, 373 (1968) and then subjecting the compound represented by formula (XIX) to step 3 and later steps in synthesis process 1 or the method in synthesis process 4: 
wherein R1 and R2 each represent C1-C6 alkyl and B, K, L, and M each are as defined above in connection with formula (I).
Synthesis Process 7
Among the compounds represented by formula (I), compounds, wherein A represents group xe2x80x94OCH2xe2x80x94, are preferably produced by the following process. 
A compound represented by formula (XX), wherein J represents a hydrogen atom or nitro and B is as defined above in connection with formula (I), is amidated by the method described in Nobuo Izumiya et al., xe2x80x9cPeptide Gosei no Kiso to Jikken (Bases and Experiments on Synthesis of Peptides)xe2x80x9d (published by Maruzen Co., Ltd.) to obtain a compound represented by formula (XXI) wherein J is as defined above and B, K, L, and M each are as defined above in connection with formula (I). Next, this compound represented by formula (XXI) is converted to a compound represented by formula (XXII), wherein J is as defined above and B, K, L, and M each are as defined above in connection with formula (I), according to the method described in Tetrahedron, 48, 4963 (1992). The compound represented by formula (XXII), wherein J represents a hydrogen atom, is nitrated according to step 3 in synthesis process 1. The compound represented by formula (XXII), wherein J represents nitro, is treated according to step 4 and later steps in synthesis process 1 to obtain the compound represented by formula (I) wherein A represents group xe2x80x94OCH2xe2x80x94.
Synthesis Process 8
Among the compounds represented by formula (I), compounds, wherein A represents group xe2x80x94SCH2xe2x80x94, are preferably produced by the following process. 
A compound represented by formula (XXIII), wherein Q represents a halogen atom and B is as defined above in connection with formula (I), is amidated by the method described in Nobuo Izumiya et al., xe2x80x9cPeptide Gosei no Kiso to Jikken (Bases and Experiments on Synthesis of Peptides)xe2x80x9d (published by Maruzen Co., Ltd.) to obtain a compound represented by formula (XXIV) wherein Q is as defined above and B, K, L, and M each are as defined above in connection with formula (I). Next, the compound represented by formula (XXIV) is reacted with 1 to 5 equivalents of potassium hydrosulfide or potassium thioacetate in a solvent not involved in the reaction (for example, ethanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, or acetonitrile), and, when potassium thioacetate is used, the reaction product is further hydrolyzed. Thus, a compound is obtained which is represented by formula (XXV) wherein B, K, L, and M each are as defined above in connection with formula (I). This reaction may be carried out at 0 to 200xc2x0 C. for 1 to 72 hr, preferably at 50 to 150xc2x0 C. for 1 to 48 hr. The compound represented by formula (XXV) is further treated in step 2 and later steps in synthesis process 7 to give the compound represented by formula (I) wherein A represents group xe2x80x94SCH2xe2x80x94.
Synthesis Process 9
Among the compounds represented by formula (I), compounds, wherein K and L each represent a bond and M represents optionally substituted phenyl or an optionally substituted, saturated or unsaturated, five-membered or six-membered heterocyclic ring containing up to two hetero atoms, are preferably produced by the following process. 
A compound represented by formula (XXVI), wherein t represents an integer of 1 or 2 and B is as defined above in connection with formula (I), and a compound represented by formula Wxe2x80x94OH, wherein W represents C1-C3 alkyl, are esterified according to the method described in xe2x80x9cJikken Kagaku Koza 22,xe2x80x9d 4th edition, edited by The Chemical Society of Japan (published by Maruzen Co., Ltd.), pp. 43-47 to give a compound represented by formula (XXVII). Next, the compound represented by formula (XXVII) is halogenated according to the method described in xe2x80x9cJikken Kagaku Koza 19,xe2x80x9d 4th edition, edited by The Chemical Society of Japan(published by Maruzen Co., Ltd.), pp. 422-438 to give a compound represented by formula (XXVIII) wherein Q represents a halogen atom and t, B, and W each are as defined above. The compound represented by formula (XXVIII) is reacted with a compound represented by formula H2Nxe2x80x94Kxe2x80x94Lxe2x80x94M in the presence or absence of a base in a solvent not involved in the reaction (for example, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, or dichloromethane) for 10 min to 48 hr, preferably 10 min to 24 hr, at xe2x88x9220 to 150xc2x0 C., preferably at 0 to 100xc2x0 C., to give a compound represented by formula (XXIX) wherein t, B, W, K, L, and M each are as defined above. The compound represented by formula (XXIX) is then reduced in the presence of palladium-carbon according to step 4 in synthesis process 1 to give a compound represented by formula (XXX) wherein t, B. W, K, L, and M each are as defined above. The compound represented by formula (XXX) is reacted in the presence or absence of a base or an acid in a solvent not involved in the reaction (for example, ethanol, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, or toluene) for 10 min to 48 hr, preferably 10 min to 24 hr, at xe2x88x9220 to 150xc2x0 C., preferably at 0 to 100xc2x0 C., to give a compound represented by formula (X) wherein t, B, K, L, and X each are as defined above. The compound represented by formula (X) may be then treated by step 5 and later steps in synthesis process 1 to give the compound repressed by formula (I) wherein K and L represent a bond and M represents an optionally substituted phenyl or an optionally substituted, saturated or unsaturated, five-membered or six-membered heterocyclic ring containing up to two hetero atoms.
Synthesis Process 10
Among the compounds represented by formula (I), compounds, wherein A represents group xe2x80x94CR1R2xe2x80x94CH2xe2x80x94 wherein R1 and R2 each represent Cl-C6 alkyl, are preferably produced by synthesizing a compound represented by formula (XXXI) according to the method described in J. Heterocycl. Chem. 7, 615 (1970) and then treating the compound represented by formula (XXXI) according to step 3 and later steps in synthesis process 1 or alternatively the synthesis process 4: 
wherein R1 and R2 each represent C1-C6 alkyl; and B is as defined above in connection with formula (I).